Major histocompatibility complex class II-expressing bone marrow megakaryocytes activate CD4(+) T cells and induce regulatory T cell fate.

While professional antigen-presenting cells drive adaptive immunity, atypical cell types can fulfill this role in the bone marrow. Megakaryocytes (MKs) are canonically recognized for platelet production, but recent studies indicate functional heterogeneity and immune potential. We found that ~20% of bone marrow MKs express Major Histocompatibility Complex (MHC) II and costimulatory receptors CD80, CD86, and CD40. These MKs process and present antigen to activate T cells in an MHC II-dependent manner. MK-T cell interactions induced TGF-β1 secretion and promoted induced regulatory T cell differentiation. Immunopeptidomics of MK MHC II receptor confirmed occupancy by exogenous peptides, demonstrating in vivo functionality. Using a model with MK-targeted deletion of MHC II (Pf4-MHC (Δ/Δ) mice), we observed altered TLR signaling, reduced bone marrow TGF-β1, and decreased numbers of hematopoietic stem cells. Together, these findings identify MHC II+ MKs as noncanonical antigen-presenting cells that modulate adaptive immunity and maintain the hematopoietic niche.